Trembath Y, Rosenberg C, Ervin JF, Schmechel DE, Gaskell P, Pericak-Vance M, Vance J, Hulette CM.
Lewy body pathology is a frequent co-pathology in familial Alzheimer's disease.
Acta Neuropathol. 2003 May;105(5):484-8.
PubMed.
Trembath et al. (1), in an analysis of 22 Alzheimer disease (AD) families, each with at least one family member with the postmortem diagnosis of dementia with Lewy bodies (DLB), examined 47 autopsy-proven cases of AD with α-synuclein immunochemistry. Four families, with either one or two brains showing Lewy body (LB) pathology, demonstrated linkage to chromosome p12 that is considered a susceptibility locus of late-onset AD (2,3), while one family with four LB-positive autopsies of patients with onset of illness between 40 and 60 years showed linkage to the AβPP gene that has been observed in early onset AD with cortical and subcortical LBs (4,5), indicating a link with the genetic basis of familial AD. In five other families with two or more LB-positive autopsies, the linkage was unknown, while the remaining 13 small families with only one LB-positive autopsy had not been screened for linkage. From these data, the authors suggest that one pathologic phenotype of DLB may be familial, with either identical phenotype in all examined family members or different coexisting pathologies in others. However, the reported data pose several open questions, which appear to be important:
1. Unfortunately, no information on the mode of inheritance in the examined AD/DLB families was given. This is of interest, since a few families with autosomal inheritance of DLB have been described (6,7,8) in which some or all affected individuals carried at least one ApoE4 allele (7,9), while there were no nucleotide alterations in the synuclein or parkin genes.
2. In the families with linkage of DLB to 12p, the prevalence of LB location was either identical within one family (family 5: neocortex; family 6: brain stem) or different (family 16: one brain neocortical, the other without LBs; family 1: limbic or negative). In family 21 linked to AβPP mutation, there were limbic, neocortical, and negative LB findings. Similar differences concerned the severity of neuritic AD pathology, ranging from Braak stages I-IV (family 6), II-IV (family 5) or IV-V (family 16, 19, 21).
The data reported by Trembath et al. (1) confirm that familial DLB exists. However, there is genetic and phenotypic heterogeneity in families linked to chromosome 12 (10, 11), as has also been reported for 12-linked late-onset AD, and in families linked to AβPP, also known from familial early onset AD due to a point mutation in the AβPP gene. The fact that there is substantial phenotypical (clinical and neuropathological) heterogeneity within and among families implies that additional clinicopathological and genetic studies are necessary to further our understanding of DLB and its relationship to AD.
References:
Trembath Y, Rosenberg C, Ervin JF, Schmechel DE, Gaskell P, Pericak-Vance M, Vance J, Hulette CM.
Lewy body pathology is a frequent co-pathology in familial Alzheimer's disease.
Acta Neuropathol. 2003 May;105(5):484-8.
PubMed.
Wu WS, Holmans P, Wavrant-DeVrièze F, Shears S, Kehoe P, Crook R, Booth J, Williams N, Pérez-Tur J, Roehl K, Fenton I, Chartier-Harlin MC, Lovestone S, Williams J, Hutton M, Hardy J, Owen MJ, Goate A.
Genetic studies on chromosome 12 in late-onset Alzheimer disease.
JAMA. 1998 Aug 19;280(7):619-22.
PubMed.
Rogaeva E, Premkumar S, Song Y, Sorbi S, Brindle N, Paterson A, Duara R, Levesque G, Yu G, Nishimura M, Ikeda M, O'Toole C, Kawarai T, Jorge R, Vilarino D, Bruni AC, Farrer LA, St George-Hyslop PH.
Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity.
JAMA. 1998 Aug 19;280(7):614-8.
PubMed.
Janssen JC, Lantos PL, Fox NC, Harvey RJ, Beck J, Dickinson A, Campbell TA, Collinge J, Hanger DP, Cipolotti L, Stevens JM, Rossor MN.
Autopsy-confirmed familial early-onset Alzheimer disease caused by the l153V presenilin 1 mutation.
Arch Neurol. 2001 Jun;58(6):953-8.
PubMed.
Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, Nee LE, O'Connell B, Pollen DA, St George-Hyslop P, Ghetti B, Nochlin D, Bird TD, Cairns NJ, Lee VM, Iwatsubo T, Trojanowski JQ.
Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes.
Am J Pathol. 1998 Nov;153(5):1365-70.
PubMed.
Wakabayashi K, Hayashi S, Ishikawa A, Hayashi T, Okuizumi K, Tanaka H, Tsuji S, Takahashi H.
Autosomal dominant diffuse Lewy body disease.
Acta Neuropathol. 1998 Aug;96(2):207-10.
PubMed.
Ishikawa A, Takahashi H, Tanaka H, Hayashi T, Tsuji S.
Clinical features of familial diffuse Lewy body disease.
Eur Neurol. 1997;38 Suppl 1:34-8.
PubMed.
Tsuang DW, Dalan AM, Eugenio CJ, Poorkaj P, Limprasert P, La Spada AR, Steinbart EJ, Bird TD, Leverenz JB.
Familial dementia with lewy bodies: a clinical and neuropathological study of 2 families.
Arch Neurol. 2002 Oct;59(10):1622-30.
PubMed.
Galvin JE, Lee SL, Perry A, Havlioglu N, McKeel DW, Morris JC.
Familial dementia with Lewy bodies: clinicopathologic analysis of two kindreds.
Neurology. 2002 Oct 8;59(7):1079-82.
PubMed.
Scott WK, Grubber JM, Abou-Donia SM, Church TD, Saunders AM, Roses AD, Pericak-Vance MA, Conneally PM, Small GW, Haines JL.
Further evidence linking late-onset Alzheimer disease with chromosome 12.
JAMA. 1999 Feb 10;281(6):513-4.
PubMed.
Scott WK, Grubber JM, Conneally PM, Small GW, Hulette CM, Rosenberg CK, Saunders AM, Roses AD, Haines JL, Pericak-Vance MA.
Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity.
Am J Hum Genet. 2000 Mar;66(3):922-32.
PubMed.
Comments
Institute of Clinical Neurobiology
Trembath et al. (1), in an analysis of 22 Alzheimer disease (AD) families, each with at least one family member with the postmortem diagnosis of dementia with Lewy bodies (DLB), examined 47 autopsy-proven cases of AD with α-synuclein immunochemistry. Four families, with either one or two brains showing Lewy body (LB) pathology, demonstrated linkage to chromosome p12 that is considered a susceptibility locus of late-onset AD (2,3), while one family with four LB-positive autopsies of patients with onset of illness between 40 and 60 years showed linkage to the AβPP gene that has been observed in early onset AD with cortical and subcortical LBs (4,5), indicating a link with the genetic basis of familial AD. In five other families with two or more LB-positive autopsies, the linkage was unknown, while the remaining 13 small families with only one LB-positive autopsy had not been screened for linkage. From these data, the authors suggest that one pathologic phenotype of DLB may be familial, with either identical phenotype in all examined family members or different coexisting pathologies in others. However, the reported data pose several open questions, which appear to be important:
1. Unfortunately, no information on the mode of inheritance in the examined AD/DLB families was given. This is of interest, since a few families with autosomal inheritance of DLB have been described (6,7,8) in which some or all affected individuals carried at least one ApoE4 allele (7,9), while there were no nucleotide alterations in the synuclein or parkin genes.
2. In the families with linkage of DLB to 12p, the prevalence of LB location was either identical within one family (family 5: neocortex; family 6: brain stem) or different (family 16: one brain neocortical, the other without LBs; family 1: limbic or negative). In family 21 linked to AβPP mutation, there were limbic, neocortical, and negative LB findings. Similar differences concerned the severity of neuritic AD pathology, ranging from Braak stages I-IV (family 6), II-IV (family 5) or IV-V (family 16, 19, 21).
The data reported by Trembath et al. (1) confirm that familial DLB exists. However, there is genetic and phenotypic heterogeneity in families linked to chromosome 12 (10, 11), as has also been reported for 12-linked late-onset AD, and in families linked to AβPP, also known from familial early onset AD due to a point mutation in the AβPP gene. The fact that there is substantial phenotypical (clinical and neuropathological) heterogeneity within and among families implies that additional clinicopathological and genetic studies are necessary to further our understanding of DLB and its relationship to AD.
References:
Trembath Y, Rosenberg C, Ervin JF, Schmechel DE, Gaskell P, Pericak-Vance M, Vance J, Hulette CM. Lewy body pathology is a frequent co-pathology in familial Alzheimer's disease. Acta Neuropathol. 2003 May;105(5):484-8. PubMed.
Wu WS, Holmans P, Wavrant-DeVrièze F, Shears S, Kehoe P, Crook R, Booth J, Williams N, Pérez-Tur J, Roehl K, Fenton I, Chartier-Harlin MC, Lovestone S, Williams J, Hutton M, Hardy J, Owen MJ, Goate A. Genetic studies on chromosome 12 in late-onset Alzheimer disease. JAMA. 1998 Aug 19;280(7):619-22. PubMed.
Rogaeva E, Premkumar S, Song Y, Sorbi S, Brindle N, Paterson A, Duara R, Levesque G, Yu G, Nishimura M, Ikeda M, O'Toole C, Kawarai T, Jorge R, Vilarino D, Bruni AC, Farrer LA, St George-Hyslop PH. Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. JAMA. 1998 Aug 19;280(7):614-8. PubMed.
Janssen JC, Lantos PL, Fox NC, Harvey RJ, Beck J, Dickinson A, Campbell TA, Collinge J, Hanger DP, Cipolotti L, Stevens JM, Rossor MN. Autopsy-confirmed familial early-onset Alzheimer disease caused by the l153V presenilin 1 mutation. Arch Neurol. 2001 Jun;58(6):953-8. PubMed.
Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, Nee LE, O'Connell B, Pollen DA, St George-Hyslop P, Ghetti B, Nochlin D, Bird TD, Cairns NJ, Lee VM, Iwatsubo T, Trojanowski JQ. Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol. 1998 Nov;153(5):1365-70. PubMed.
Wakabayashi K, Hayashi S, Ishikawa A, Hayashi T, Okuizumi K, Tanaka H, Tsuji S, Takahashi H. Autosomal dominant diffuse Lewy body disease. Acta Neuropathol. 1998 Aug;96(2):207-10. PubMed.
Ishikawa A, Takahashi H, Tanaka H, Hayashi T, Tsuji S. Clinical features of familial diffuse Lewy body disease. Eur Neurol. 1997;38 Suppl 1:34-8. PubMed.
Tsuang DW, Dalan AM, Eugenio CJ, Poorkaj P, Limprasert P, La Spada AR, Steinbart EJ, Bird TD, Leverenz JB. Familial dementia with lewy bodies: a clinical and neuropathological study of 2 families. Arch Neurol. 2002 Oct;59(10):1622-30. PubMed.
Galvin JE, Lee SL, Perry A, Havlioglu N, McKeel DW, Morris JC. Familial dementia with Lewy bodies: clinicopathologic analysis of two kindreds. Neurology. 2002 Oct 8;59(7):1079-82. PubMed.
Scott WK, Grubber JM, Abou-Donia SM, Church TD, Saunders AM, Roses AD, Pericak-Vance MA, Conneally PM, Small GW, Haines JL. Further evidence linking late-onset Alzheimer disease with chromosome 12. JAMA. 1999 Feb 10;281(6):513-4. PubMed.
Scott WK, Grubber JM, Conneally PM, Small GW, Hulette CM, Rosenberg CK, Saunders AM, Roses AD, Haines JL, Pericak-Vance MA. Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am J Hum Genet. 2000 Mar;66(3):922-32. PubMed.
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